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Acupuncture or Metformin for Insulin Resistance in Women With PCOS (PIAII)

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ClinicalTrials.gov Identifier: NCT02647827
Recruitment Status : Recruiting
First Posted : January 6, 2016
Last Update Posted : August 15, 2019
Sponsor:
Collaborators:
Karolinska University Hospital
Peking University
Information provided by (Responsible Party):
Elisabet Stener-Victorin, Karolinska Institutet

Brief Summary:
The hypothesis is that acupuncture is equally effective as metformin (both treatments combined with lifestyle management) in improving whole body glucose homeostasis in insulin resistant women with polycystic ovary syndrome (PCOS), and that both are superior to lifestyle management alone. The investigators hypothesize that acupuncture and metformin induce ovulation and improve hyperandrogenism, as well as health related quality of life (HRQoL) and symptoms of anxiety and depression. Although equally effective (acupuncture and metformin), the investigators hypothesize that acupuncture is associated with less negative side-effects. The investigators also hypothesize that these treatments have the potential to restore epigenetic and molecular alterations in target tissues (endometrial-, adipose-, and skeletal muscle tissue) and thus have the potential to prevent the development of type 2 diabetes (T2D).

Condition or disease Intervention/treatment Phase
Polycystic Ovary Syndrome Insulin Resistance Hyperandrogenism Other: Lifestyle management Device: Acupuncture Drug: Metformin Phase 2

Detailed Description:

Specific Aims The purpose of the study is to perform a randomized controlled trial of women with PCOS, comparing the effectiveness of lifestyle management alone, and in combination with acupuncture or metformin treatment on whole body glucose homeostasis, with the ultimate goal to prevent the development of type 2 diabetes.

Primary aim

1. To determine the clinical effectiveness of 4 months of 1) electroacupuncture + lifestyle management and 2) metformin + lifestyle management, compared to 3) lifestyle management only, for improvement of insulin sensitivity as measured by HOMA-IR, by the insulin response to glucose assessed by calculating the area under the curve (AUCinsulin) during the oral glucose tolerance test (OGTT), and by glucose regulation (assessed by analyzing Hba1c levels).

Secondary aims

  1. To evaluate changes in secondary metabolic measures, including fasting insulin, c-peptide, glucose, and adipokines, calculation of HOMA-B (i.e. the Islet β-cell function) and the c-peptide index, assessment of the adipokines and lipid profile, body size and proportions and body fat distribution.
  2. To determine changes in genome-wide gene expression and DNA methylation profiles related to insulin sensitivity in fat, muscle and endometrial tissue biopsies, and biomarkers in whole blood.
  3. To evaluate endocrine measures including menstrual pattern and ovulation frequency, circulating hormones (sex steroids, AMH, gonadotropins), and excretion of metabolites of sex steroids in urine.
  4. To determine changes in women's HRQoL, symptoms of anxiety and depression, dieting and eating patterns, and negative side-effects.
  5. To evaluate the cost-effectiveness of the different treatments.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 303 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Acupuncture or Metformin for Insulin Resistance in Women With Polycystic Ovary Syndrome: A Randomized Controlled Trial
Study Start Date : December 2015
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : December 2021


Arm Intervention/treatment
Active Comparator: Lifestyle management
All women will receive lifestyle management instructions at the baseline visit, before randomization.
Other: Lifestyle management
All women will receive lifestyle management instructions at the baseline visit, before randomization. The lifestyle management involves one initial counselling session in connection with the baseline visit, which includes information about the importance of weight management, healthy diet and physical activity.

Active Comparator: Acupuncture + lifestyle management
Three treatment per week (4 weeks) and thereafter 2 times per week during 12 weeks.
Other: Lifestyle management
All women will receive lifestyle management instructions at the baseline visit, before randomization. The lifestyle management involves one initial counselling session in connection with the baseline visit, which includes information about the importance of weight management, healthy diet and physical activity.

Device: Acupuncture
Disposable, single-use, sterilized CE marked needles made of stainless steel, 0.25 x 30 mm and 0.30 x 40/50 mm will be inserted to a depth of 15-40 mm in segmental acupuncture points located in abdominal and leg muscles, with innervations corresponding to the ovaries and the pancreas. Two sets of acupuncture points will be alternated every second treatment.

Active Comparator: Metformin + lifestyle management
Oral metformin 500 mg three times daily, in total 1500 mg per day.
Other: Lifestyle management
All women will receive lifestyle management instructions at the baseline visit, before randomization. The lifestyle management involves one initial counselling session in connection with the baseline visit, which includes information about the importance of weight management, healthy diet and physical activity.

Drug: Metformin
Oral metformin 500 mg three times daily, in total 1500 mg per day. To reduce gastrointestinal side-effects of metformin, the dose will be slowly escalated starting with 500 mg daily during the first week, increasing to 500 mg twice per day during the second the week, and 500 mg three times daily, morning, lunch and dinner from the third week in total 16 weeks including the 3 weeks step-up phase (i.e. 4 months).




Primary Outcome Measures :
  1. Changes from baseline to after 4 months in HOMA-IR [fasting insulin (μU/mL) × fasting glucose (mmol/L)] / 22.5) [ Time Frame: 4 months ]
    Changes from baseline to after 4 months of treatment in HOMA-IR [fasting insulin (μU/mL) × fasting glucose (mmol/L)] / 22.5) between 1) acupuncture + lifestyle management and 2) metformin + lifestyle management compared to 3) lifestyle management only.

  2. Changes from baseline to after 4 months of treatment in HbA1c [ Time Frame: 4 months ]
    Changes from baseline to after 4 months of treatment in HbA1c between 1) acupuncture + lifestyle management and 2) metformin + lifestyle management compared to 3) lifestyle management only.

  3. Changes from baseline to after 4 months of treatment in insulin response to glucose during the oral glucose tolerance test (OGTT) [ Time Frame: 4 months ]
    Changes from baseline to after 4 months of treatment in insulin response to glucose during the OGTT (AUC using the trapezoidal rule) between 1) acupuncture + lifestyle management and 2) metformin + lifestyle management compared to 3) lifestyle management only.


Secondary Outcome Measures :
  1. Changes from baseline to after 4 months and again 4 months after last treatment in secondary metabolic measures [ Time Frame: 8 months ]
    Changes in secondary metabolic measures with calculation of e.g. HOMA-B

  2. Changes from baseline to after 4 months and again 4 months after last treatment gene expression and DNA methylation profiles related to insulin sensitivity in fat, muscle and endometrial tissue biopsies, and biomarkers in whole blood. [ Time Frame: 8 months ]
    Changes in mRNA gene expression and DNA methylation expression and biomarkers in whole blood.

  3. Changes from baseline to after 4 months and again 4 months after last treatment in menstrual pattern. [ Time Frame: 8 months ]
    Changes in menstrual pattern per month.

  4. Changes from baseline to after 4 months and again 4 months after last treatment in circulating reproductive hormones. [ Time Frame: 8 months ]
    Changes in circulating circulating reproductive hormones.

  5. Changes from baseline to after 4 months and again 4 months after last treatment in women's HRQoL. [ Time Frame: 8 months ]
    Changes in women's HRQoL measured with polycystic ovary syndrome questionnaire (PCOSQ) and short form-36 (SF36) two validated questionnairs.

  6. Changes from baseline to after 4 months and again 4 months after last treatment in women's symptoms of anxiety and depression. [ Time Frame: 8 months ]
    Changes in women's symptoms of anxiety and depression measured with the self-reported version of the Comprehensive Psychopathological Rating Scale for Affective Syndromes (CPRS-S-A).

  7. Changes from baseline to after 4 months and again 4 months after last treatment in women's dieting and eating patterns. [ Time Frame: 8 months ]
    Changes in women's dieting and eating patterns assessed with Three-Factor Eating Questionnaire (TFEQ-R21), and Questionnaire of Eating and Weight Patterns-Revised (QEWP-R).

  8. Cost-effectiveness of the different treatments throughout the study. [ Time Frame: 8 months ]
    Cost-effectiveness of the different treatments by calculation of e.g. treatment visits, time for patient and with EuroQol-5 dimension (EQ-5D).



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 40 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion criteria - women with PCOS:

  1. Age 18 to 40 years
  2. Body mass index (BMI) ≥25 to ≤40 given that 95% of all women with PCOS with a BMI ≥25 are insulin resistant (71,72).
  3. PCOS diagnosis according to Rotterdam criteria 2003 (73), with at least two of the following three symptoms: Clinical signs of hyperandrogenism (hirsutism or acne); oligo/amenorrhea; and/or polycystic ovaries (PCOS). Hirsutism is defined as a self-reported Ferriman-Gallwey (FG) score ≥8 (≥5 Asian) (74,75). Acne is defined by a positive response to the question Do you have acne? Oligomenorrhea is defined as an intermenstrual interval >35 days and <8 menstrual bleedings in the past year. Amenorrhea as <3 cycles per year. PCO is defined by transvaginal ultrasound with ≥12 follicles 2-9 mm and/or ovarian volume ≥10 ml in one or both ovaries.
  4. Willing to sign the consent form.

Inclusion criteria - controls:

Controls should have BMI >25 to <40, regular cycles with 28 days ± 2 days, and no signs of hyperandrogenism. They are excluded if they have menstrual irregularities, signs of hyperandrogenism (FG >4), or evidence of PCO morphology on ultrasound.

Exclusion criteria for all women

  1. Age >40
  2. Exclusion of other endocrine disorders such as non-classic congenital adrenal hyperplasia (17-hydroxyprogesterone < 3nmol/L), androgen secreting tumors or suspected Cushing's syndrome.
  3. Having known renal disease (creatinine clearance < 60 mL/min), hepatic insufficiency, autoimmune disorders or cancer.
  4. Any acute condition with potential to alter renal function or cause tissue hypoxia.
  5. Type I diabetes.
  6. Pharmacological treatment (cortizon, antidepressant, other antidiabetic treatment such as insulin and acarbose, hormonal contraceptives, hormonal ovulation induction or other drugs judged by discretion of investigator) within 12 weeks. Depo Provera or similar within 6 months.
  7. Hypersensitivity to metformin hydrochloride or to any of the excipients.
  8. Blood pressure >160 / 100 mmHg
  9. Pregnancy or breastfeeding the last 6 months
  10. Acupuncture the last 2 months
  11. Daily smoking and alcoholic intake
  12. Language barrier or disabled person with reduced ability to understand the information given.

In total 50 controls will be matched at baseline (age, weight and BMI) to women with PCOS. Controls will undergo screening and baseline visit, but will not be randomized to any treatment.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02647827


Contacts
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Contact: Elisabet Stener-Victorin, PhD +46705643655 elisabet.stener-victorin@ki.se
Contact: Berit Legerstam, Study nurse +46851773782 berit.legerstam@karolinska.se

Locations
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China
Peking University Recruiting
Beijing, China, 100871
Contact: Jie Qiao, Professor    +8615611908108    jie.qiao@263.net   
Contact: Haolin Zhang, PhD    +8613911533466    zoe@bjmu.edu.cn   
Sweden
Karolinska University Hospital Recruiting
Stockholm, Sweden, 17176
Contact: Berit Legerstam, Study nurse    +46851773782    berit.legerstam@karolinska.se   
Contact: Liselotte Blomberg, Study nurse    +46851773782    liselott.blomberg@karolinska.se   
Principal Investigator: Elisabet Stener-Victorin, PhD         
Sub-Investigator: Angelica Linden-Hirschberg, Professor         
Sub-Investigator: Sebastian Gidlöf, PhD         
Sponsors and Collaborators
Karolinska Institutet
Karolinska University Hospital
Peking University
Investigators
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Principal Investigator: Elisabet Stener-Victorin, PhD Karolinska Institutet

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Elisabet Stener-Victorin, PhD, Associate Professor, Karolinska Institutet
ClinicalTrials.gov Identifier: NCT02647827     History of Changes
Other Study ID Numbers: EudraCT: 2015-004250-18
2015-004250-18 ( EudraCT Number )
First Posted: January 6, 2016    Key Record Dates
Last Update Posted: August 15, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Keywords provided by Elisabet Stener-Victorin, Karolinska Institutet:
Acupuncture
Metformin
Glucose metabolism
Hba1c
Additional relevant MeSH terms:
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Polycystic Ovary Syndrome
Hyperandrogenism
Insulin Resistance
Syndrome
Disease
Pathologic Processes
Hyperinsulinism
Glucose Metabolism Disorders
Metabolic Diseases
Ovarian Cysts
Cysts
Neoplasms
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Gonadal Disorders
Endocrine System Diseases
46, XX Disorders of Sex Development
Disorders of Sex Development
Urogenital Abnormalities
Adrenogenital Syndrome
Congenital Abnormalities
Metformin
Hypoglycemic Agents
Physiological Effects of Drugs